1. Field of the Invention
The present invention relates generally to the fields of molecular genetics and neuroendocrine cellular biology. More specifically, the present invention relates to a mammalian drosophila period-like gene that exhibits properties of a circadian pacemaker.
2. Description of the Related Art
In response to daily environmental cues, the physiology and behavior of all living organisms from bacteria to humans are controlled by circadian rhythms driven by endogenous oscillators (Dunlap, 1993, Takahashi, 1995). Alteration of the circadian rhythm in humans can lead to behavioral changes as typified by jet lag and sleep disorders including those associated with shift work (Arendt and Broadway, 1987, Vignau et al., 1993, Wehr, 1996). In addition, certain pathophysiologies are known to fluctuate according to circadian rhythms such as the increased likelihood of a myocardial infarction occurring in the morning, and winter seasonal affective disorder (Kraft and Martin, 1995, Swaab et al., 1996, Teicher et al., 1997).
Extensive physiological and behavioral studies have determined that the endogenous clock is characterized by a cycle approximately 24 hours in duration. When organisms are placed under invariant environmental conditions, this clock is self-sustaining, similar to a pacemaker. This endogenous clock is further distinguished by its ability to be entrained, i.e., synchronized by environmental cues such as light and temperature cycles (Pittendrigh, 1993, Takahashi, 1995).
Primary culture of suprachiasmatic nucleus (SCN) neurons and suprachiasmatic nucleus ablation and transplantation studies indicate that the circadian clock is cell autonomous, and that in mammals it is located primarily in a part of the hypothalamus known as the suprachiasmatic nucleus, (Ralph et al., 1990, Welsh et al., 1995) and is situated close to the base of the brain. There are independent circadian oscillators located in the retina (Tosini and Menaker, 1996). In constant darkness, the various circadian functions such as maintenance of body temperature, formation of urine, and secretion of cortisol become asynchronous (Aschoff, 1969). This suggests that there may be several independent clocks that each regulate specific circadian rhythms. However, studies of the hamster tau mutant suggest that the molecular components that constitute the various clocks may be related (Tosini and Menaker, 1996).
The molecular mechanisms that constitute these oscillators in mammals are unknown. 2-deoxy [.sup.14 C]-glucose uptake experiments (Schwartz and Gainer, 1977) and studies using protein and RNA synthesis inhibitors suggest that circadian rhythms can be controlled by periodic expression of genes (Takahashi and Turek, 1987, Raju et al., 1991). A mutation in a single gene, clock, alters the phase of the circadian clocks in mice (King et al., 1997). Whether clock is expressed in a periodic pattern is not known.
In Drosophila, two genes period (per) and timeless (tim), are essential components of the circadian clock (Reppert and Sauman, 1995). A heterodimer of Per and Tim proteins is thought to regulate the circadian process by creating a negative feedback loop controlling per and tim expression (Zeng et al., 1996). Two lines of evidence, the oscillatory nature of the per expression, and the phenotype of per mutants, portray the central role of the per gene in the circadian machinery of insects (Konopka and Benzer, 1971, Citri et al., 1987, Hardin et al., 1990, Hall, 1996). Immunohistochemical analysis of rat brain using a Drosophila Per antibody revealed staining in the suprachiasmatic nucleus, suggesting the possibility of a conserved mammalian Per protein (Siwicki et al., 1992). However, in over a decade since per was first isolated from Drosophila melanogaster (Bargellow et al., 1984; Citri et al., 1987), no mammalian per homologue has yet been reported.
The prior art is deficient in the lack of a mammalian ortholog to the drosophila period gene that exhibits properties of a circadian pacemaker. The present invention fulfills this longstanding need and desire in the art.